Process for preparing desacetoxycephalosporins

Abstract

A penicillin sulfoxide is heated in the presence of silylating agent to produce a novel silyl ester azetidine-2-sulfenate which, by treatment with acid, is converted to a desacetoxycephalosporin compound.

I claim: 
     
       1. A process for preparing a desacetoxycephalosporin from a penicillin sulfoxide of the formula ##SPC7## in which R 3  is hydrogen and R 4  is hydrogen; C 1  -C 8  alkanoyl; azidoacetyl; cyanoacetyl; haloacetyl; ##EQU16## in which Ar is phenyl, thienyl, furyl, pyrrolyl, or phenyl substituted with from one to three substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, C 1  -C 3  acyloxy, hydroxy, C 1  -C 3  alkyl, C 1  -C 3  alkoxy, cyano, and nitro; ##EQU17## in which Ar' is phenyl, pyridyl, or substituted phenyl as defined above, and Y is oxygen or sulfur; ##EQU18## in which Ar is as defined above, and B is C 1  -C 3  acyloxy, hydroxyl, carboxyl, esterified carboxyl, --CN, --N 3 , --NH 2 , or --NHR in which R is benzyloxycarbonyl, C 1  -C 4  alkoxycarbonyl, cycloalkoxycarbonyl, triphenylmethyl, ##EQU19## or 2,2,2-trichloroethoxycarbonyl; (3-sydnone)-C 2  -C 3  alkanoyl; ##SPC8##   in which R' is hydrogen or methoxy; 2-(1H-tetrazol-1-yl)acetyl; or R 3  and R 4  taken together with the nitrogen atom to which they are bonded are phthalimido, a cyclic imide moiety of a C 3  -C 12  dicarboxylic acid, 2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl, or 2,2-dimethyl-3-nitroso-5-oxo-4-phenylimidazolidin-1-yl; and R 2  is hydrogen, C 1  -C 6  alkyl, 2,2,2-trihaloethyl, 2-iodoethyl, benzyl, nitrobenzyl, tetrahydropyranyl, 9-fluorenyl, succinimidomethyl, phthalimidomethyl, methoxybenzyl, dimethoxybenzyl, cyanomethyl, nitrophenyl, dinitrophenyl, 2,4,6-trinitrophenyl, bis(p-methoxyphenyl)methyl, triphenylmethyl, benzhydryl, benzyloxymethyl, C 2  -C 6  alkanoyloxymethyl, C 2  -C 4  alkanoyl, phenacyl, or a radical of the formula ##EQU20## in which each R 1  independently is c 1  -C 4  alkyl or phenyl; which comprises heating the penicillin sulfoxide in an inert, substantially anhydrous solvent to a temperature of from about 75°C. to about 150°C. in the presence of from about 1.1 to about 4 equivalents of a silylating agent of the formula   a. ##EQU21## in which each R 1  independently is C 1  -C 4  alkyl, or phenyl, R'" is hydrogen, C 1  -C 4  alkyl, or phenyl, and X is ##EQU22## in which J is hydrogen or --Si(R 1 ) 3 , or X is --CW 3  in which each W independently is hydrogen, trifluoromethyl or C 1  -C 3  alkyl;   b. ##EQU23## in which R 1  and W are as herein defined; and c. Z--Si(R 1 ) 3     in which R 1  is as herein defined and Z is halogen, C 2  -C 3  alkenyloxy, C 1  -C 3  alkyl--SO 3  --, --O--Si(R 1 ) 3 , --S--Si(R 1 ) 3 , or ##EQU24## in which R 5  is hydrogen or c 1  -C 3  alkyl, and R 6  is C 1  -C 4  alkyl or --Si(R 1 ) 3 , or R 5  and R 6  taken together with the nitrogen atom to which they are bonded form a heterocyclic ring having 5 or 6 atoms, up to 3 of which, in addition to the already-defined nitrogen atom, independently are nitrogen, sulfur, or oxygen; and simultaneously or subsequently treating the reaction mixture in an acidic medium selected from the group consisting of a mineral acid, a sulfonic acid, and a Lewis acid.     
     
     
       2. Process of claim 1, wherein the silylating agent is selected from the group consisting of N,O-bis-(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-trimethylsilylacetamide, N-methyl-N-trimethylsilylacetamide, N-trimethylsilyl-N,N'-diphenylurea, propenoxytrimethylsilane, trimethylsilyl methane sulfonate, trimethylchlorosilane, dimethylchlorosilane, hexamethyldisilazine, N-trimethylsilyl-t-butylamine, N-trimethylsilyldiethylamine, N-trimethylsilylimidazole, hexamethyldisiloxane, hexamethyldisilthiane and mixtures of any of the above. 
     
     
       3. Process of claim 2, wherein the acidic medium comprises a sulfonic acid. 
     
     
       4. Process of claim 3, wherein the acidic medium comprises a C 1  -C 12  hydrocarbonsulfonic acid. 
     
     
       5. Process of claim 4, wherein the acidic medium comprises methanesulfonic acid. 
     
     
       6. Process of claim 5, in which the silylating agent comprises a mixture of hexamethyldisilazane and trimethylchlorosilane. 
     
     
       7. Process of claim 5, in which the silylating agent comprises N-trimethylsilylacetamide. 
     
     
       8. Process of claim 5, in which the silylating agent comprises N,O-bis-(trimethylsilyl)acetamide. 
     
     
       9. Process of claim 3, wherein R 2  is hydrogen or a radical of the formula ##EQU25## and the reaction mixture containing the resulting free acid desacetoxycephalosporin is treated with a lithium compound to produce the corresponding lithium salt of the desacetoxycephalosporin. 
     
     
       10. Process of claim 9, in which the lithium compound is lithium acetate. 
     
     
       11. Process of claim 3, in which R 3  is hydrogen and R 4  is phenylacetyl or phenoxyacetyl.